Photodynamic therapy is a method for treatment of tumors and other tissue alterations by light in combination with a light sensitive substance, a so-called photosensitizer, and oxygen contained in the tissue. Such a sensitizer or one of its metabolic precursors is administered to a patient. This sensitizer or metabolic precursor selectively accumulates in the tumor. After a certain waiting time, the tumor and the surrounding healthy tissue are irradiated with light of an appropriate wavelength. Photophysical processes generate toxic substances, so-called reactive oxygen species, from oxygen contained in the tissue. These reactive oxygen species selectively damage the tumor, because the sensitizer has selectively accumulated in the tumor tissue.
In comparison to a surgical treatment, photodynamic therapy has the advantage of a non-invasive or only slightly invasive treatment. In particular, there is no need, for security reasons, for the removal of a large amount of healthy tissue near the tumor. Irradiation with light is from 10 to 100 minutes at a typical light intensity of from 100 mW/cm2 to 100 mW/cm2. The tissue is therefore only slightly heated. Photodynamic therapy of tumors normally needs only a single treatment, it is however possible to repeat the treatment. As light of normal wavelength is used, the impact on the patient is relatively small in comparison to a “classical” treatment.
The disadvantage of photodynamic therapy is the relatively small penetration depth of light of only a few millimeters. Therefore, in most cases, only tumors in the initial stage or of flat shape may be treated effectively. Such tumors suitable for photodynamic therapy are for example skin tumors, such as actinic keratodermia or basalioma, but also warts. The use of lasers and fiber-optic light guides also permits the treatment of tumors inside the body if their surface is accessible by an endoscope.
Photodynamic therapy of tumors inside the body today is only rarely used, in most cases only for palliative purposes in the oesophagus, in cancers of the bile duct or the gall bladder or in brain tumors.
Photodynamic therapy was already investigated in Munich at the beginning of the twentieth century. It came into wider use only in the eighties after improvements of photosensitizers and the use of lasers. Typical ranges of application are the treatment of tumors in the urinary bladder, at the surface of the head, in the oral cavity, in the larynx, in the lung, in the bile duct and in the genital region.
The fundamental physical process of photodynamic therapy has several steps and needs the presence of oxygen that is present in sufficient amounts in most cells. A molecule of the photosensitizer absorbs a light photon and is excited into its first excited singlet state. If the lifetime of this singlet state is long enough, the probability of a transition into the excited triplet state by inter-combination increases. As optical transitions from this excited triplet state into the ground state are very improbable, its lifetime is very long. This allows the contact with many molecules in the surroundings. In the case where it encounters a molecule with a triplet ground state, energy exchange is possible wherein both molecules change into the singlet state. One of the rare molecules with a triplet ground state is molecular oxygen. As the energy of the excited sensitizer molecule is higher than the energy needed for a transition of oxygen into an excited singlet state, such a transition is possible. The excited singlet oxygen has a very long lifetime with respect to an optical transition into its ground state. As the excited singlet oxygen is very reactive, it can damage cell constituents in the vicinity by oxidation. A necrosis is induced or, by an impact on the mitochondria membrane, an aptotose.
In most cases, porphyrins are used as photosensitizers. They are activated by exposure to red light at wavelengths between 630 nm and 635 nm. 5-Aminolevulinic acid or its methyl ester, metabolic precursors of protoporphyrin, are also sometimes used. Protoporphyrin selectively initiates synthesis of porphyrin in tumour cells. Modern photosensitizers may be activated at higher wavelengths with the advantage of a bigger penetration depth of the light into the tissue. Photosensitizers normally show fluorescence and are therefore also used in fluorescence diagnosis of tumors.
Optimal wavelengths for photodynamic therapy are situated between 600 nm and 1500 nm. At shorter wavelengths, the tissue is not transparent enough for the radiation and at longer wavelengths the energy of the radiation is too low. The penetration depth in tissue is 4 mm at a wavelength of 630 nm and 8 mm at a wavelength of 700 nm.
The use of phthalocyanine dyes as photosensitizers in photodynamic therapy was first described by E. Ben-Hur and I. Rosenthal in “The phthalocyanines: a new class of mammalian cells photosensitizers with a potential for cancer phototherapy”, International Journal of Radiation Biology 47, 145-147 (1985) and subsequently by C. M. Allen, W. M. Sharman and J. E. van Lier in “Current status of phthalocyanines in the photodynamic therapy of cancer”, Journal of Porphyrins and Phthalocyanines 5, 161-169 (2002) and by E. Ben-Hur and W.-S. Chan in “Phthalocyanines in Photobiology and their Medical Applications”, Volume 19, pages 1-35 by K. M. Kadish, K. M. Smith and R. Guilard (Editors), “The Porphyrin Handbook”, Academic Press San Diego (2003), ISBN 0-12-393229-7. The photodynamic activity and the adsorption of sulphonated phthalocyanines on membranes is described by A. A. Pashkovskaya, E. A. Sokolenko, V. S. Sokolov, E. A. Kotova and Y. N. Antonenko in “Photodynamic activity and binding of sulfonated metallophthalocyanines to phospholipid membranes: Contribution of metal-phosphate coordination”, Biochimica et Biophysica Acta 1768, 2459-2465 (2007).
The synthesis of the often-used zinc phthalocyanine dye of formula (I)
and its photodynamic activity as photosensitizer is described by J. Griffith, J. Schoefield, M. Wainwright and S. B. Brown in “Some observations on the Synthesis of Polysubstituted Zinc Phthalocyanine Sensitizers for Photodynamic Therapies”, Dyes and Pigments 33, 65-78 (1997).
Unsubstituted phthalocyanine dyes as photosensitizers for photodynamic therapy are described in patent application WO 92/01,753. The central atom of the phthalocyanine dye is silicium or aluminum.
Unsubstituted phthalocyanine dyes as photosensitizers for photodynamic therapy are also described in patent application WO 95/06,688. The central atom of the phthalocyanine dye is silicium or aluminum.
Unsubstituted phthalocyanine dyes as photosensitizers for photodynamic therapy are also described in U.S. Pat. No. 5,484,778. The central atom of the phthalocyanine dye is silicium.
Substituted phthalocyanine dyes as photosensitizers for photodynamic therapy are also described in patent application WO 95/05,818. The central atom of the phthalocyanine dye is a diamagnetic metal atom or silicium.
Substituted phthalocyanine dyes as photosensitizers for photodynamic therapy are described in patent application WO 02/090,361. The central atom of the phthalocyanine dye is silicium, zinc or aluminum.
An ideal photosensitizer for photodynamic therapy should be highly soluble in the cell medium, non-toxic and very efficient. It should accumulate very selectively only in tumors. In the case where it is toxic, it should be rapidly metabolized to harmless, non-toxic compounds which may easily be eliminated from the body.
There is therefore still a need for improved photosensitizers for photodynamic therapy having these properties. In particular, the absorption maximum of the compounds should be above 630 nm, preferably above 650 nm.